Ovarian cancer is associated with the highest mortality rate of all gynecologic malignancies in US and with an overall 5 years survival rate of 30-40%. Although the majority of tumors initially respond to standard treatments combining surgery and chemotherapy with platinum-based drugs such as cisplatin, but the majority of treated patients acquire multidrug resistance and succumb to their disease due to relapse. It is believed that cancer initiating cells (CICs) also known as cancer stem cells play a major role in tumor recurrence and metastatic spread. Therefore, to inhibit relapse and increase patients' survival rate, it is crucial to design a treatment strategy that during the early stage treatment eradicates both differentiating ovarian cancer cells and CICs. Based on this premise, the primary objective of this research is to develop a targeted therapeutic system that can effectively kill both differentiating cancer cells and CICs and demonstrate not only eradication of the primary tumors but also inhibition of relapse. Solid tumors have complex pathophysiology and factors such as degree of capillary leakiness, extracellular proteins, tumor heterogeneity and tumor cell density significantly limit distribution and efficacy of therapeutic molecules. As a result, a subpopulation of differentiating cancer cells and/or CICs may survive the treatment. To overcome these obstacles and achieve the objective, we have developed a novel highly efficient targeted-shielded nanotechnology platform (vector) that utilizes passive, active and transcriptional targeting mechanisms in order to achieve high anticancer activity at the tumor site with minimal impact on normal tissues. Our live animal imaging and tumor regression studies illustrate that the developed system passively accumulates in tumors, is actively picked up by tumor cells, efficiently transfects and expresses reporter genes specifically in tumors but not other tissues and after gene directed enzyme/prodrug therapy completely eradicates two different types of aggressive xenograft drug resistant ovarian tumors. Furthermore, after careful screening through a panel of suicide genes, we have identified one enzyme/prodrug system that has the potential to inhibit relapse. It is our hypothesis that the novel targeted vector can effectively deliver suicide genes into a panel of xenograft and syngeneic ovarian tumors without affecting normal organs and result in eradication of the primary tumors and inhibition of relapse. We believe that this research is of high significance because it addresses an important problem; i.e., cancer relapse. Once developed, this nanotechnology-based system can be used as a platform for therapy of other types of cancer. The proposed studies in this grant application are designed to first isolate CICs and validate the ability to target and kill these cells followed by n extensive in vivo biodistribution, therapy response and toxicity studies to demonstrate the effectiveness of the system in treating various ovarian tumors. The outcome of this research could ultimately have a significant impact on cancer patients' survival rate because it will be the first nanomedicine that could effectively inhibit ovarian cancer relapse.